The processes of septation and thinning of the large saccules that comprise the gas-exchange region of the immature lung (termed alveolarization) are highly conserved across species as a means of matching the architecture of the gas-exchange region of the lung with the magnitude of gas exchange needed to meet metabolic demands. Our recent studies provide data consistent with the notions that 1) there is a "critical" period in which the process of septation must occur or it will never occur, 2) there are means in addition to septation of immature saccules, by which alveoli are formed and these various means of increasing gas-exchange surface are under different regulatory controls (corticosteroid and thyroid hormones, sex, nutrition), and 3) dexamethasone accelerates alveolar wall thinning and differently affects division by the replicating cells of the alveolar wall. We now propose to use newly available experimental models that we have developed, or with which we have considerable experience, and morphometric techniques, which do not have the defects of methods previously used by us and others, to test these notions. In particular we will use 3- dimensional reconstruction of pulmonary acini in rats to a) determine if new alveoli are formed between age 14 and 60 days, b) to test the hypothesis that there is more than one method of forming alveoli, and c) to determine if the methods of forming alveoli are under different controllers. Our second aim is to use a recently available, theoretically sound, and experimentally validated method of enumerating cells with which we have substantial experience, to test the hypothesis that the developmentally regulated cell composition of the alveolar wall can be experimentally modulated, to delineate some of the modulating agents and events, and, to determine if the "catch-up" increase in lung cells, following an experimentally slowed rate of increase, is achieved with a normal or abnormal composition of cells. We believe the data obtained 1) will lead to more mechanistic studies that will provide a molecular explanation of the events that are determinative to the alveolarization process, and, 2) will foster studies on humans that will increase our understanding of lung development in the perinatal period thereby improving the care of infants.